Soluble guanylate cyclase stimulator praliciguat promotes ischemic leg reperfusion in db/db mice

Abstract

Lower-limb peripheral artery disease (PAD) is a prevalent and challenging complication of diabetes, requiring innovating therapies. Praliciguat is an orally available stimulator of soluble guanylate cyclase (sGC) reported to have favorable effects on metabolic and hemodynamic endpoints in preclinical and clinical studies, suggesting the potential for benefit in PAD. We evaluated the effect of praliciguat on hindlimb ischemia recovery in a mouse model of diabetes and investigated the molecular mechanism of sGC stimulation. Hindlimb ischemia was induced in db/db mice by ligation and excision of the left femoral artery. Praliciguat 10 mg/kg/day ( n = 10 mice) or vehicle ( n = 10) were administered in the diet for 31 days starting 3 days before surgery. Foot perfusion was assessed with a Laser Doppler Imager and reported as a ratio in the ischemic versus non-ischemic limb. Ischemic leg function was assessed with a 4-point scale: 0, plantar/toe flexion in response to tail traction; 1, plantar but not toe flexion; 2, no flexion; 3, foot dragging. Ischemic foot perfusion and function were better 28 days after surgery in praliciguat than in vehicle treated mice (mean ± SD: perfusion 1.05 ± 0.23 vs. 0.38 ± 0.16; P < 0.0001; function 1.14 ± 0.36 vs. 1.73 ± 0.80; P = 0.03). Praliciguat did not impact angiogenesis. Arteriolar diameter was higher (9.88 ± 0.96 vs. 8.57 ± 0.64 μm; P = 0.004) and ICAM-1 expression lower (186 ± 41 vs. 403 ± 177% of healthy muscle; P = 0.005) in the ischemic limb of mice treated with praliciguat than with vehicle. Praliciguat attenuated accumulation of oxidative pro-angiogenic and pro-inflammatory muscle fibers. In cultured myoblasts praliciguat significantly downregulated Myh2 and Cxcl12 mRNA expression. Conditioned medium from praliciguat-treated myoblast decreased ICAM-1 mRNA expression in HUVECs. These results suggest that praliciguat restored perfusion and function in the ischemic muscle of db/db mice by increasing arteriolar diameter and decreasing ICAM-1 expression in endothelial cells via downregulation of Cxcl12 in myocytes.